PROJECT SUMMARY/ABSTRACT Persistent human papillomavirus (HPV) infection is responsible for over 30,000 new cases of cancer annually in the United States (US). HPV infection can be prevented by immunization, but 12 years after being recommended for use, HPV immunization rates among US adolescents remain suboptimal. While uptake of other vaccines recommended for 11-12 year-olds is at or near 90%, only 43% of adolescent boys and girls are up-to-date for HPV vaccination. Prior efforts to improve HPV vaccine uptake have followed standard best practices for immunization programs, including education provision for parents and adolescent patients, and Health Belief Model-inspired appeals to disease severity. One key barrier to improving HPV vaccine uptake is that healthcare providers often do not recommend this vaccine with the same strength as they do for other adolescent vaccines. Continued low uptake of HPV vaccine indicates that new systems-level approaches, beyond standard public health education campaigns, are needed. These systems-level approaches ? incorporating the healthcare practice and provider as well as the patient - must be designed and packaged in a way to address the quality of, and context around, provider recommendations. Our research team has developed and pilot-tested an intervention package ? TweenVax ? designed to improve HPV vaccine uptake at the practice-, provider-, and patient/parent-level. Evaluation of TweenVax identified key elements for expansion to improve the provision and strength of provider recommendations. Gaps remain in terms of how best to address missing or substandard provider recommendations, including addressing moment-to-moment patient and data flow and various points of intervention during the clinic visit including desk check-in through clinical examination and vaccination and follow-up appointment scheduling. Enhancements to the TweenVax intervention will include improvements in practice-level communication in the context of patient flow and additional training for non-clinical staff, development of enhanced training modules for clinical staff, including interactive experiential training and provision of continuing education credits, and updates to the content and presentation of the TweenVax tablet- and web-based educational program. The proposed multi-phase study will 1) assess, using ethnographic observations and in-depth interviews, both best practices and deficiencies in all clinical aspects of the adolescent healthcare encounter, with findings used to refine existing intervention tools to improve HPV vaccination of 11-12 year-olds; and 2) evaluate the efficacy of our comprehensive intervention in improving HPV vaccine uptake among 11-12 year-old girls and boys in Georgia and Tennessee. This assessment, through a three-arm trial, will provide the opportunity to assess the efficacy of the intervention package as a whole, as well as to determine the efficacy of individual components (e.g. practice-/provider-level components independent of patient/parent-level components).